Compounds that induce isoforms of glutathione S-transferase with properties of a critical enzyme in defense against oxidative stress

Compounds that upregulate enzymes that play critical roles in protection against free radical damage might be useful in treating diseases in which free radicals are pathological. To identify critical enzymes and their upregulators, compounds that were not free radical scavengers were screened for the ability to increase the IC50 of the human neuronal cell line IMR-32 for hydrogen peroxide. Subsequently, enzymes upregulated by compounds that increased the IC50 were identified. All of the compounds identified that increased the IC50 also increased the specific activity of glutathione S-transferase (GST). in addition, compound-caused increases in the specific activity of GST correlated with compound-caused increases in the IC50, the expected behaviour if GST was a critical enzyme. The CST isoform composition changed on upregulation, suggesting the upregulation of isoforms with anti-free radical activities. Structural features of compounds concurrently increasing the IC50 and upregulating GST were identified. (C) 1999 Academic Press.